Prodromes predict attacks of hereditary angioedema: Results of a prospective study
Authors: Iris Leibovich‐Nassi, Hava Golander, Avner Reshef
Journal: Allergy (2022)

Hereditary angioedema (HAE) is a lifetime disease characterized by repetitive bouts of tissue edema.1 Early signs, symptoms, and perceptions (prodromes) are manifested by subjective and objective signals, preceding attacks by several hours.2, 3 Using a new HAE-specific instrument, we have recently shown that patients can identify prodromes and are able to predict oncoming attacks.4 However, that study was retrospective, which might have been affected by recall bias. In the present study, a cohort of 48 HAE patients prospectively reported four events of prodromes followed by attack, attacks not preceded by a prodrome and incidents with only a prodrome. Pre-defined domains (clusters of body locations) and scalable dimensions (pain, severity, impairment, and functionality), time of onset and termination were assessed in each episode.3, 4 (Statistical methods are described in the Appendix S1). The study was approved by the ethics committees of Tel-Aviv University, Sheba Medical Center, and Barzilai Medical center. All patients signed an informed-consent form. Mean age was 35.25 years (SD ± 16.4), Median 30.0 (age range 10–70) and 27 (56.25%) were females. Mean age of onset was 8.3 years and age at diagnosis 10.9 years (2.7 years diagnostic gap) (Table S1). We received reports on 119 prodromes and 192 attacks. The majority experienced a prodrome before at least one of their attacks, and 64% affirmed that they can predict an oncoming attack by having a prodrome. (Table S1). Significant differences were found between prodromes and attacks across all dimensions of the pre-defined clusters of body locations. Statistical analysis verified that prodromes could be discriminated from attacks for all parameters. (Table 1) Positive correlations were found between the same attributes of prodromes and attacks, most notably in the abdominal and extremity clusters (Table S2, Figure S1A–E). Mean duration of prodromes was significantly shorter than attacks, and prodromes overlapped the attack in 24.3% of cases. The analysis indicates that individuals who experience a prodrome had higher risk for having an attack in the same region. Sensitivity of the prodrome as a predictor of attack was 95% to 99%, and specificity 18% to 64%. (Table 2). HAE prodromes represents a continuity of pathophysiologic events, initiated by the activation of the bradykinin-forming cascade and ending with a breach in vascular endothelial integrity.2, 5 (Figure S2) In this study, we aimed to capture the critical elements of prodromes and their association with consequent attacks and evaluate their predictive power as an early warning sign.2-4 The HAE-EPA instrument reliably captures patient's experience by using the same metrics, and the prospective design better reflects patients' experience in real-time, which may have been missed in our previous study. The study highlights the predictive value of prodromes as forecasters of attacks.2-4 It affirms that patients can clearly distinguish prodromes from attacks. The positive correlations support our basic assumption that prodromes could predict attack location and severity, which is particularly germane in the abdomen. High-intensity attack was predated by a high-intensity prodrome. This substantiate our observation on inter-personal differences between subjects4 Mean disease duration of the cohort (27 years) may surmise that the study subjects were experienced patients, who could recognize early pre-attack cues. Although the study was not designed to investigate on-demand medication use, there is evidence that early treatment of attacks, even at the prodromal stage, may enhance their resolution.6, 7 Therefore, experienced patients can use prodromes as an efficient strategy in managing attacks by employing early interventions. Such approach was already used in other diseases with relapsing–remitting pattern.8 In conclusion, the study ascertained that HAE patients can distinguish prodromes from attacks and a prodrome may predict attack in the same location. Having a prodrome increase the likelihood of subsequent attack, alerting the patients and assisting in early initiation of therapy. None. Stanley Steyer Graduate Scholarship Fund (Tel Aviv University) and CSL- Behring Fellowship Fund. No conflict of interest declared. Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.